Sickle Cell DiseaseTimothyL. McCavit, MD*AuthorDisclosureDrMcCavithasdisclosednonancialrelationshipsrelevanttothisarticle. Thiscommentarydoesnotcontain a discussion ofanunapproved/investigativeuseofa commercial product/device.EducationalGapIntheUnitedStates, sicklecelltraitiscarriedby7%to8%ofpeopleofAfricanan-cestry,andthesicklehemoglobinopathiesareestimatedtoaffect90,000to100,000people.Objectives Aftercompletingthisarticle, readersshouldbeableto:1. Understand how the sickle hemoglobin mutation leads to the various manifestationsofsicklecelldisease(SCD).2. IdentifycommonhealthmaintenanceneedsforchildrenwithSCD.3. RecognizethecommonacutecomplicationsofSCDandtheirtreatment.4. AssesstherisksandbenetsofthecommontreatmentmodalitiesforSCD.5. DiscusstheimprovedprognosisforchildrenwithSCD.EpidemiologyThe World Health Organization estimates that 7% of the worlds population carries a he-moglobin (Hgb) mutation and that 300,000 to 500,000 children are born each year withseverehemoglobinopathy.ThesickleHgb(HgbS)mutationoccurredindependentlyatleast four times (three times in sub-Saharan Africa and once in India or the Arabian pen-insula) in regions with endemic malaria. In the heterozygous state, the sickle mutation pro-vides protection against infection by the falciparum species of malaria and likely confersasurvival advantage, leadingtoits continuedhighprevalenceinsomepopulations ofsub-Saharan Africa and the Middle East/India. In the United States, sickle cell trait is car-ried by 7% to 8% of people of African ancestry, and the sickle hemoglobinopathies are es-timated to affect 90,000 to 100,000 people. (1) US newborn screening data suggest that1 in 2,500 newborns is affected by a formof sickle cell disease(SCD).NomenclatureSCD refers to a group of heterogeneous disorders that areunied by the presence of at least one b globin gene affectedbythesicklemutation(position6, b-globingene; codonGAG changes to codon GTG, coding for glutamic acid in-stead of valine). Homozygotes for the sickle mutation havesickle cell anemia (SS) or Hgb SS disease, which accounts forw60% to 65% of SCD.When inherited with the sickle mutation in a compoundheterozygous state, otherb-globin gene mutations lead tootherdistinctformsofSCD.Themostcommonoftheseis HgbC, which, when coinherited with the sickle mutation,leads to sickle hemoglobin-C disease, accounting for 25% to30% of all SCD. Coinheritance of ab thalassemia mutationwith the sickle mutation leads to sickle b0thalassemia (Sb0)or sickle b thalassemia, which account for 5% to 10% of allSCD (b0indicates nob globin production;b indicates di-minishedb globin production).AbbreviationsACS: acute chest syndromeHgb: hemoglobinHgbS: sickle hemoglobinHSCT: hematopoietic stem cell transplantationHU: hydroxyureaIPD: invasive pneumococcal diseasePAH: pulmonary artery hypertensionPCV13: pneumococcal conjugate vaccinePROPS: Prophylactic Penicillin StudyRBC: red blood cellSCD: sickle cell diseaseSS: sickle cell anemiaSb0: sickleb0thalassemiaTCD: transcranial DopplerTRJV: tricuspid regurgitant jet velocityVOC: vaso-occlusive crises*DivisionofHematology-Oncology, DepartmentofPediatrics, UniversityofTexasSouthwesternMedicalCenteratDallas, Dallas,TX;CenterforCancerandBloodDisorders, ChildrensMedicalCenterDallas, Dallas, TX.Article blooddisordersPediatricsinReviewVol.33No.5May2012 195Otherlesscommonb-globinmutationsthatleadtoSCD when coinherited with HgbS include Hgbs OArab,D, andE. WhendiscussingpatientswithSCD, precisenomenclature is important because of the phenotypic var-iability between the various forms.It shouldalsobenotedthat thetermsicklerisviewed as a derogatory term by many in the SCD cli-nician and patient community and is inappropriate touse in communication among clinicians. More appro-priate terminology would bea patient with sickle celldisease.PathophysiologyThe sickle mutation leads to the replacement of hydro-philic glutamic acid by a hydrophobic valine. The pres-ence of the hydrophobic valine residue allows HgbS topolymerize inthe deoxygenatedstate. Inadditiontolow oxygen tension, low pH and an increased concentra-tion of HgbS within the red blood cell (RBC) encouragepolymer formation. HgbS polymerization ultimatelycauses RBCs totakeonthecharacteristicsickleshapein a reversible fashion. Repeated episodes of polymeriza-tion andsickling can cause an RBC to be irreversiblysickled. Inthe circulation, these stiff, nondeformablesickled cells can lead to vaso-occlusion, with resultant tis-sue ischemia. As a result of or in addition to HgbS po-lymerization, other pathophysiologic mechanisms in patientswithSCDhavebeenobserved, includingactivationofthevascularendothelium,leukocytosis,leukocyteactiva-tion, platelet activation, and oxidative stress fromtissue re-perfusion. Additionally,reducedRBCdeformabilityandinjuryof theRBCcytoskeletoncausedbythepresenceof HgbS polymers ultimately result in both intravascularandextravascularhemolysis.Inthepast10years,ithasbeen suggested that nitric oxide depletion secondary to in-travascularhemolysismaycontributetocertaincompli-cationsof SCD, suchaspulmonaryarteryhypertension(PAH), although this postulate is controversial. (2)(3)DiagnosisBeforenewbornscreening, thediagnosis of SCDwasmadeonlyafterapotentiallydevastatingcomplicationpromptedmedical attention. Justicationof newbornscreeningfor SCDwas providedbytheProphylacticPenicillinStudy (PROPS) in1986(see below), andsince then, universal newborn screening with Hgb elec-trophoresis (Table 1) or other methods has become thestandard in the United States. Certain states also provideconrmation of an SCD electrophoresis result by DNAsequencing.Aswithmostgeneticconditions,prenataldiagnosis of a fetus with SCD is possible in therst tri-mester through chorionic villus sampling or in the sec-ond trimester through amniocentesis.HealthMaintenanceSCDis medically complex, affecting virtually any organ inthe body, so children born with SCD benet from well-coordinated, comprehensive, multidisciplinary care. Thiscare occurs ideally through regular interactions with botha primary care provider and a pediatric hematologist. Psy-chologists, social workers, andexpert nursingsupportplay important roles as patients and families adjust to lifewithSCDandits complications. Additionally, othersubspecialtyexpertiseinSCDis important, includingneurology, pulmonology, nephrology, radiology, oph-thalmology, otorhinolaryngology, general surgery, andanesthesiology.InadditiontotheelementsofroutinehealthmaintenancehighlightedinTable2, commonchronic problems and activities discussed at routine visitsinclude enuresis, sleepandsleep-disorderedbreathing,jaundice, mental health and adjustment to chronic disease,andsportsparticipation. Intheteenageyears, fosteringself-care, responsibility, andreadinessfortransitiontoadult care become the focus.ClinicalPresentationEffectsonBloodA variety of hematologic abnormalities typify SCD. Ane-miaistheprimaryhematologicmanifestationof SCD,with the severity determined by genotype (Table 3), inaddition to the specic patients rates of hemolysis, eryth-ropoiesis, andplasmavolumeexpansion. (4)Afterthetransition to adult b globin expression occurs in therstTable 1. Newborn Screen Results forCommon HemoglobinopathiesNewbornScreeningResult InterpretationF, A NormalF, A, S SicklecelltraitF, S SS, Sb0, orS-HPFHF, S, C HgbS-CdiseaseF, S, A SicklebDthalassemiaF, A, S, Barts SicklecelltraitwithathalassemiatraitF b-thalassemiamajorb thalassemia trait is not diagnosed in the newborn period with mostcurrent newborn screening techniques. AHgbA; CHgbC; FfetalHgb; SHgbS; S-HPFHsickle with hereditary persistence of fetal Hgb.blooddisorders sicklecelldisease196PediatricsinReviewVol.33No.5May2012year of life, children with SCD typically maintain stablebaseline Hgb levels with signicant uctuations occur-ringusuallyduringacutediseasecomplications. Addi-tionally, aleukocytosis withtypical total whitebloodcell countsof 15,000to25,000/mm3isobserved. Amildthrombocytosis is alsocommonamongpatientswithSCD,withaverageplatelet countsof 400,000to475,000/mm3.InfectionPNEUMOCOCCUSANDPROPHYLACTICPENICILLIN. ApredilectiontoinfectionbytheencapsulatedorganismStreptococcus pneumoniae has longbeenrecognizedinchildrenwithSCD, particularlythosewithSS, duetofunctional asplenia. Beforeattemptsatprophylaxis, theincidenceof invasivepneumococcal disease(IPD)wassixepisodes/100patientyears, withapeakintherst3years of life. Beginninginthelate1970s andearly1980s, the pneumococcal polysaccharide vaccine becamestandard for children with SCD. In 1986, the landmarkPROPS clinical trial revealed an 84% decrease in the riskof IPD in children receiving daily prophylactic penicillin,compared with those receiving placebo. (5)The PROPS II study attempted to answer the ques-tion of whether prophylactic penicillin could be discon-tinued safely at 5 years of age. (6) The number of IPDevents was unexpectedlylowduringthestudyperiod,so a difference in the rates of IPD between groups couldnot bedemonstratedclearly. This ndinghas ledtoa variable practice among sickle cell centers with someTable 2. HealthMaintenanceTimelineforChildrenWithSCDIntervention/Activity TimingComprehensivemedicalevaluation(withahematologist,wherepossible)Firstvisitby2moofage34/yuntilage512/yafterage5Geneticcounseling Firstvisit, re-educateasneededPneumococcalprophylaxisTwicedailyprophylacticpenicillin AssoonaspossiblePCV13series 2, 4, 6, and1215moPneumococcalpolysaccharidevaccine Firstdoseat2yofageHaemophilusinuenzaetypebvaccine 2, 4, 6, and1215moMeningococcalvaccine(MCV4) 1stdoseat24monthsofageorolder;2totaldosesatleast8weeksapartInuenzavirusvaccine Firstafter6moafterbirth, annuallythereafterEducationonspleenpalpationandsigns/symptomsofsplenicsequestrationFirstvisitandeveryvisitthereafteruntilage35yTCDultrasonography* Firstscreenat2yofageIfnormal, repeatannuallyuntilage16Ifconditional, repeatevery36moIfabnormal32, initiatetransfusionsAsthmascreening Screeninghistoryat1yofage, thenannuallyPFTsat6yofage, thenevery5yGrowthandmaturationassessment AtleastannuallyAssessmentofschoolperformance AtleastannuallyuponschoolentryAssessmentforsickleretinopathybyanophthalmologist Annuallybeginningat10yofageEvaluateforsicklenephropathybycreatinine, urinalysis,urineprotein/creatinineratioormicroalbuminuriaAnnuallybeginningat10yofageCounselingontransitiontoadultcare Annuallybeginningat1315yofageScreeningperformedatsomecenters Ifdone, idealtimingisunknownHistory, physicalorradiographforavascularnecrosisoffemoralheadsHistoryandphysicalforobstructivesleepapneaEchocardiographyforelevatedTRJVMRIforsilentstrokeandcerebralvasculopathyPFT=pulmonary function test, TCD=transcranial Doppler.*For patients with SS and Sb0.Disagreement among experts about the necessity of PFT screening.Limited evidence base to support a specic method or timing.blooddisorders sicklecelldiseasePediatricsinReviewVol.33No.5May2012 197recommending daily penicillin for life (or at least untilage18years), whereas others recommendcessationof prophylaxis at age 5 years. Similarly, the role of pen-icillininpatientswithHgbSCandothermildgeno-types is controversial.The heptavalent pneumococcal conjugate vaccine, li-censed in 2000, has led to a further 70% decrease in theincidence of IPD, now estimated to be 0.3 to 0.5/100patient years. (7) After heptavalent pneumococcal con-jugate vaccine licensure, nonvaccine serotypes emergedas the most common cause of IPD, particularly serotype19A. Pneumococcal conjugate vaccine (PCV13), licensedin 2010, includes 19A and other currently prevailing sero-types. Current standard practice should include daily pro-phylactic penicillin beginning before 2 months of age, thePCV13 series as recommended for all children, and at leasttwo doses of pneumococcal polysaccharide vaccine, withtherst dose at 2 years of age.FEVERMANAGEMENT. Becauseof theriskof IPD,anyfever (typicallydenedas 38.3C) is treatedasa medical emergency for children with SCD. Urgent eval-uation of all febrile episodes, including physical examina-tion, complete blood count, and blood culture, is ofutmost importance. Although hospitalization for observa-tionissometimesnecessary, patientswithSCDevaluatedfor fever without a source who lack certain high risk features(white blood cell count >30,000/mm3or 40C, ill-appearing) may be managed safelyas anoutpatient after intravenous administration ofanempiric, antipneumococcal antibiotic(eg, ceftriaxone).Other factors that must be considered in deciding whetherto discharge a patient from the emergency department in-clude the age of the patient, the ability of the family to re-turn promptly for recurrent fever or clinical deterioration,and the availability of close follow-up.APLASTIC CRISIS. Infection by parvovirus B19 leadsto a maturation arrest for RBC precursors in the bonemarrow for w10 to 14 days. In hematologically normalchildren, this arrest in RBC production is not problem-aticbecauseofthe120-daylifespanofnormal RBCs.InSCD,however,theRBClifespanisbetween10and20 days, so cessation of RBC production for 10 to 14 dayscan lead to profound anemia. Signs and symptoms of pro-found anemia, including pallor, fatigue, decreased ac-tivity, altered mentation, and poor feeding, are typicalof aplasticcrises. Laboratoryevaluationrevealssevereanemia with reticulocytopenia and occasional thrombo-cytopenia. The management of an aplastic crisis includestransfusion support as needed until reticulocyte recoveryhas occurred. Familymembers of patients withSCDwho are experiencing an aplastic crisis should be evalu-ated if they have SCD and no previous history of parvo-virus infection.AcutePainVASO-OCCLUSIVE CRISIS. Severe, episodic pain istheclinical hallmarkof SCD. Commonlyreferredtoas vaso-occlusive crises (VOC), these episodes can occurfrom infancy until old age, although they increase in fre-quencythroughoutchildhoodwithapeakinthemid20s. ThepathophysiologicmechanismformostVOCis bone marrow ischemia with resultant infarction. Riskfactors for more frequent VOC include severe genotype(SS or Sb0), increasing age, and high baseline Hgb level.On the other hand, a high baseline fetal Hgb concentra-tion is protective. VOCs are triggered commonly by in-fection, emotionalstress,or exposuretocold,wind, orhigh altitude. The episodes may occur in many locationsthroughout the body, although the lower back, legs, andarms are most common. Using the frequency of inter-actions with the health-care system as a proxy for painfrequencyandseveritymayvastlyunderestimatetheproblemof paininSCD. Itis, therefore, crucial thathealth-careprovidersspecicallyassesspainoccurringat home during routine visits.Table 3. HematologicParametersfortheCommonFormsofSCDName GenotypeTypicalBaselineValuesHgb, g/dL Reticulocytes, % MCVSicklecellanemia SS 69 1020 Normal*Sicklehemoglobin-Cdisease SC 911 310 LownormaltoslightlylowSickleb-zerothalassemia Sb069 1020 LowSickleb-plusthalassemia SbD1012 25 LowMCVmean corpuscular volume.*Unlessa thalassemia trait is coinherited with SS.blooddisorders sicklecelldisease198PediatricsinReviewVol.33No.5May2012The severity and duration of VOCs vary from minorpainlastingminutestoexcruciatingpainlastingdays.Examination of a patient having a VOC may reveal er-ythema, edema, joint effusions, or point tenderness, butnoneof thesesignsmaybepresent andtheyarenotrequiredfor thediagnosis. Aminor decreaseinHgbconcentration frombaseline and an increased whiteblood cell count are common but nonspecic laboratoryfeatures.Theapproachtotreatingsevereacutepain,sadly,hasnotchangedindecades. Opioidanalgesics, anti-inammatorymedications, andintravenous uidsre-mainthemainstays of treatment. RBCtransfusions,however, do not aid in the resolution of severe VOCs.Recognitionandtreatmentof psychosocial contribu-tors to acute and chronic pain are other key elementsto VOC management. Many pain crises can be treatedathomewithdistractionandothercopingbehaviorsinadditiontooral painmedications. PreventionofVOCscanbeaidedbytheavoidanceofprecipitatingfactors, the use of hydroxyurea (HU, see below),and maintenance of intravascular volume through oraluid intake.DACTYLITIS. DactylitisisaspecictypeofVOCthatoccurs in infants and young children with SCD, especiallySS. Dactylitis is denedby tender, erythematous, andedematous hands or feet (Fig 1). It occurs in 25% of infantsby 1 year of age and 40% by 2 years of age, although sig-nicant variability in the prevalence has been noted amongstudies. Principles of dactylitis management do not differfromotherVOCs; analgesicsandintravenous uidsarekey. Dactylitis before 1 year of age was identied as oneof three prognostic factors used to predict severe outcome(frequent VOCs, frequent acutechest syndrome[ACS],acute stroke, or death) in a large cohort study of pediatricpatients with SCD in the United States, although thisnd-ing could not be replicated in a large independent pediatriccohort study.PulmonaryComplicationsACUTECHESTSYNDROME. TheverytermACSsug-gests an incomplete understanding of this phenomenon.Clinically, ACS is dened by a new pulmonary inltrate(Fig 2) on chest radiograph in addition to one or moreof the following: fever, tachypnea, dyspnea, hypoxia,and chest pain. ACS is a common and potentially lethalcomplicationofSCD.TheincidenceofACSishighest(25episodes/100patientyears)inchildrenbetween2and 5 years of age. When the underlying cause of ACSwasinvestigatedindetail includingbronchoscopy,45%ofpatientshadnoidentiablecause, whereasinfectioncaused 30% of cases. The most common infectious causesof ACS included Chlamydia pneumoniae (28% of infec-tions), viral infection (22%), and Mycoplasma pneumoniae(20%). Pulmonaryinfarctionandfat embolismcaused16% and 8% of all ACS cases, respectively. The pathogen-esis of ACSlikelyvaries, dependingonthecause, butcommonly includes inammation, pulmonary vascularocclusion, ventilation/perfusion mismatch, airway hyper-reactivity, and pulmonary edema.The treatment of ACS includes supplemental oxygen,empiricantibiotics(includingamacrolideforcoverageof atypical pathogens), bronchodilators, and careful man-agement of analgesiaandintravascular volume. Bloodtransfusionisanotherfundamental treatmentforACS.A decrease in Hgb level from baseline and an increasingFigure 1. Dactylitisischaracterizedbytender, erythematous,and edematous hands or feet. Courtesy of Doernbecher ChildrensHospital, Portland, Oregon.Figure 2.Chestradiographofan18-month-oldinfantwithSSandsevereACSwithdiffusebilateralinltrates.blooddisorders sicklecelldiseasePediatricsinReviewVol.33No.5May2012 199supplemental oxygen requirement are common indica-tions for transfusioninACS. SimpletransfusionmaybeadequateformildtomoderateACS,butexchangetransfusionshouldbe consideredearly inthe courseof progressive or severe ACS.In addition to transfusion, supportive respiratory care,uptoandincludingmechanical ventilationandextra-corporeal membrane oxygenation, may be necessary inseverecases. Finally, corticosteroidshavebeenshownto reduce the severity of ACS hospitalizations. Unfortu-nately, corticosteroid use is complicated by a high rate ofrebound VOC, so if used at all, corticosteroids shouldbe reserved for the most severe cases.ASTHMA. Asthma is prevalent in children with SCD,as in the general population, affecting nearly 20% of pa-tients. In SCD, a diagnosis of asthma is associated withhigher rates of ACS, VOC, and early death. The mecha-nism by which asthma inuences the severity of SCD isunclearbut couldrelatetoinammation,ventilation-perfusionmismatching,orothermechanisms.Becauseof thestrengthof theSCD/asthma association, pa-tientswithSCDshouldbescreenedforasthmaonanannual basis by history and physical examination begin-ning at 1 year of age. Additionally, some groups recom-mend screening with pulmonary function testing at leastevery 5 years, beginning at 6 years of age. Patients withSCD with persistent asthma also should be followed by a pul-monologist, regardless of severity.PULMONARY ARTERY HYPERTENSION. PAH is a severecomplication of SCD that typically occurs in adulthood.Its pathogenesis may relate to nitric oxide depletion sec-ondary to release of free Hgb into the plasma fromchronicintravascularhemolysis.SymptomsofPAHmayincludeexertional dyspnea, fatigue, andsyncopal events. Rightheart catheterization classically has been required for thediagnosis of PAH, although an elevated tricuspid regurgi-tant jet velocity (TRJV) on echocardiography is correlatedwithcatheter-determinedpulmonaryarterypressures.Thus, echocardiography for TRJV is used commonly as ascreening test for PAH in adults with SCD, and, althoughcontroversial,hasbeensuggestedasascreeningtestforchildren with SCD as well. Abnormal TRJVs have becomesynonymous with PAHin some segments of the literature,but rightheartcatheterizationisstill recommendedfora denitive diagnosis and before treatment of PAH.NeurologicManifestationsSTROKE. ChildrenwithSSandSb0havelongbeenrecognized as being at risk for acute stroke. The risk ofstroke is 10% in therst 20 years of life, with a peak in-cidence between 4 and 8 years of age. (8) Most strokes inSCD are ischemic in nature, with hemorrhagic stroke ac-counting for less than 10% of the total. The presentingsymptoms of acute stroke in SCDinclude hemiparesis, fa-cial droop, aphasia, and more generalized symptoms, in-cluding stupor and, rarely, seizure. Acute stroke symptomsmay mimic a VOCin a young child reluctant to use a pain-ful limb. The pathogenesis of acute stroke is incompletelyunderstood but includes a vasculopathy marked by hyper-trophy of the intima and media layers of the large arteriesin theanteriorcerebralcirculation(primarilythemiddlecerebral arteries).The evaluation of a patient suspected of experiencingacute stroke should include a careful history and neuro-logic examination; emergent radiographic evaluation byMRI or computed tomography followed by MRI whenMRI is not immediately available; and a laboratory eval-uation, including blood count, reticulocyte count, Hgb Spercentage, and blood group and screen.The principle underlying the treatment of acute strokeis the rapid reduction of the Hgb S percentage. This goalmaybeachievedthroughsimpleRBCtransfusionorpartial manual exchange, although automated exchangetransfusion with erythrocytopheresis reduces the Hgb Spercentagemoreefcientlyandis widelyregardedasstandard practice. This treatment frequently leads to res-olution or a marked dimunition in neurologic symptomswithin 24 to 48 hours.Thelong-termoutcomeof acutestrokeisvariable;many patients lack signicant motor impairment butmay demonstrate impaired executive functioning. A sec-ond stroke is very likely without the use of regular RBCtransfusions to suppress the Hgb S percentage, and evenwith a chronic transfusion regimen (see below), w20% ofacute stroke victims will experience a second acute stroke.For this reason, hematopoietic stem cell transplantation(HSCT)maybeanoptimal therapyforchildrenwhohave a history of acute stroke when a suitable donor isavailable (see below).PRIMARYSTROKEPREVENTION. The terrible burdenof acute stroke in patients with SS and Sb0has drivenresearch dedicated to primary stroke prevention. In theearly 1990s, transcranial Doppler (TCD) ultrasonogra-phy was shown to predict risk of acute stroke in SS andSb0, with an abnormal TCD examination representinga40%riskofstrokeinthesubsequent3years.Inthelandmark Stroke Prevention Trial in Sickle Cell Anemia,children identied to be at high risk by TCD were ran-domlyassignedtomonthlybloodtransfusions versusblooddisorders sicklecelldisease200PediatricsinReviewVol.33No.5May2012observation, with a 90% decrease in the rate of stroke ob-served in the transfusion group. (9) Hence, annualscreening with TCD has become standard care for chil-drenwithSSandSb0. Thedurationoftransfusionisindenite, although current studies are addressingwhether patients may be transitioned safely to HU to pre-vent stroke.SILENTSTROKE. In the past decade, silent stroke hasbeenrecognizedas animportant probleminchildrenwith SS and Sb0. Silent stroke is dened by the pres-enceof ndings onMRI suggestiveof oldcerebralinfarction, typically small areas of gliosis, without a corrob-orating clinical history of acute stroke symptoms. Silentstrokes are associatedstrongly withneurocognitivedecits and are a risk factor for subsequent acute stroke.Most studies have revealed that silent strokes occur inw30% of children (10) with SS and Sb0, leading to es-timates of the cumulative prevalence of central nervoussystem infarct events (acute and silent stroke) of w40%in this population. Regular blood transfusions are un-der study to determine whether they may decrease therisk of acute stroke in patients who haveexperiencedsilent stroke.COGNITIVE IMPAIRMENT. Not surprisingly, patientswith SCD with a history of acute stroke or silent strokehave high rates of neuropsychological dysfunction. Eventhe SCD population that has not been affected by acuteor silent stroke has a high rate of a neuropsychologicaldysfunction that worsens with age, including decits ingeneral intelligence, attentionandexecutivefunction-ing, memory, language, andvisual-motorperformancecompared with matched controls. The result may be dif-culty at school and in other tasks requiring executive func-tioning. Early evaluation and intervention in schoolsettings may improve outcomes for this at-risk population.OtherClinicalSequelaeSplenicSequestrationRapid enlargement of the spleen with resultant trappingof the blood elements is known as acute splenic seques-tration and occurs in w30% of children with SS by 5 yearsof age, with mostrst episodes occurring before 2 yearsof age. Children with SC disease tend to develop splenicsequestration at 10 years of age or older. Splenic seques-tration was a common cause of mortality among childrenwith SCD before the 1980s. Education of family mem-bersindailyspleenpalpationisnowstandardcareandhas increased the detection of sequestration and markedlydecreased mortality.Evaluation of a child with splenic sequestration willreveal splenomegaly,aHgbvaluebelowbaseline, andthrombocytopenia, becauseall bloodelementswill betrappedinthe enlargedspleen. The management ofan initial splenic sequestration episode typically includescautious transfusiontoHgbvalues between7and9gr/dL. Areductioninspleensizefrequentlyoccurs1to3days after initial presentationandmayleadto2to 3gr/dLincreasesinHgb,aphenomenon knownasauto-transfusion.Approximately one-half of patients will experience re-currenceof splenicsequestration. Splenectomyis per-formed commonly after a second or third sequestrationepisode, although some centers chronically transfuse af-fectedinfants until 2years of agebeforeundertakingsplenectomy.CholelithiasisSCD is a chronic hemolytic anemia, and when Hgb is re-leasedfromtheRBC,bilirubinisproduced,leadingtojaundice. Ultimately, this increasedbilirubinis storedinthegall bladderandcanprecipitatetoformstones.Presenting signs and symptoms of cholelithiasis in SCDinclude right upper quadrant or epigastric abdominalpain, jaundice, andvomiting. Incidentally discovered,asymptomaticgallstonesmaybeobservedwithoutre-quiringintervention. Symptomatic stones or stonesobstructing the common bile duct commonly requirecholecystectomy. Alaparoscopicapproachisnowstan-dardfor cholecystectomy, whichreduces thedurationof postoperative pain and hospitalization. See below foradditional notes on the surgical management of patientswith SCD.PriapismPriapism is a prolonged, painful erection of the penis withtypical onset in the early morning hours. It can occur intwo forms: prolonged, an episode of 4 hours duration,andstuttering, self-limitedepisodes that canoccur inclusters. InSCD, priapismisthoughttobecausedbysickling of RBCs in the corpora cavernosa of the penis,leadingtosludgingandanincreaseinintrapenilepres-sure. (11) This effect, inturn, leads tolocal acidosisandworseningdeoxygenation, whichleads tofurthersickling in a vicious cycle that causes further outow tractobstruction and severe pain.Priapismcanoccurasyoungas3yearsof age, andw30% of boys will have an episode by age 15. If a pro-longed episode is left untreated,brosis of the cavernosamay develop, leading to permanent erectile dysfunction.Treatment of an acute episode of priapism may includeblooddisorders sicklecelldiseasePediatricsinReviewVol.33No.5May2012 201aggressive analgesia and pharmacologic efforts to decreasethe vascular engorgement of the cavernosa through ag-ents such as pseudoephredrine and etilefrine. Aspirationandirrigationof thecavernosabyaurologistmaybenecessary for prolongedepisodes. Bloodtransfusionsand oxygen are of unproven benet for acute episodesof priapism.Prevention of priapismis understudied, althoughnightly pseudoephedrine or etilefrine have been reportedto achieve some success in case series or uncontrolled tri-als.Gonadotropinreleasinghormoneanalogsalsohavebeen used to prevent recurrent priapism. The effects ofHUandchronic bloodtransfusionfor preventionofpriapism are largely unreported.SurgeryMajor surgery places a child with SCD at risk of compli-cations, including ACS. To that end, perioperative trans-fusiontoincreasetheHgbconcentrationanddecreasethe Hgb S percentage is considered standard care for ma-jor surgeries. Additionally, measures such as incentive spi-rometry, carefully titrated analgesia, oxygen therapy, andclose inpatient observation may help decrease the riskof postoperative SCD-related complications. The roleofpreoperativetransfusionforminorsurgeryinclud-ingtonsillectomy/adenoidectomyiscontroversial,buttransfusion may be safely avoided for some patients un-dergoing such procedures.TherapeuticsHydroxyureaHUistheonlymedicationapprovedbytheFoodandDrugAdministrationfor the treatment of SCD. HUuseforchildrenwithSCDhasbeenreviewedrecently.(12) HU was developed originally as a chemotherapeuticagent for certainleukemias andmyeloproliferativedis-eases, but in the early 1980s, HU was recognized to in-creaseexpressionof fetal Hgb. Fetal Hgbwas knowntoinhibit the polymerizationof HgbS, the primarymechanism underlying the SCD pathogenesis. HU alsomay act through a relative myelosuppression with a de-crease in circulating neutrophils, cells whose role in thepathogenesisof someSCDcomplicationshasrecentlybeen recognized.In clinical trials for adults with SCD, HU was showntomarkedly reduce the rate of VOCs, ACS, bloodtransfusions, and all-cause hospitalizations. In addition,long-term follow-up studies have revealed HU to con-fer a survival advantage for adults with SS and Sb0. InchildrenwithSCD, thepublishedexperiencewithHUislessextensive,althoughclinical trialswithHUhavebeen conducted in children as young as 9 to 18 monthsof age.A randomized clinical trial of HU for infants with SCD(BABY-HUG) was completed recently. (13) AlthoughHU failed to improve the primary outcomes of kidneyandspleenfunction, adecreasewas observedintherates of hospitalization, blood transfusion, ACS, dacty-litis, and other VOCs for infants on HU compared withthoseonplacebo. Thereis alsosomeevidencethatHU may reduce conditional and even abnormal TCDvelocities.The toxicity prole for HU has shown it to be tolerablewith minimal toxicities other than the risk of mild myelo-suppression. Thus, regular monitoring of blood counts isrequired while on HU. HU is theorized to be a teratogenas well and is contraindicated in pregnant women. Someconcerns haveexistedinboththepatient andcliniciancommunity that HU, as a chemotherapeutic agent, mayinduce genetic changes that could lead to myelodysplasia,leukemia, or other malignancy, yet these complicationshave never been attributed to HU in an actual patientwithSCD. Importantly, recent analyses of peripheralbloodmononuclear cells have not demonstratedim-paired DNA repair mechanisms or increased mutationsin children on HU compared with other patients withSCD.In summary, HU is an important therapeutic optionfor childrenwithSCD. Historically, HUwas reservedonlyforchildrenwithsevereorfrequentcomplicationsof SCD, but as suggested by the authors of the recentlypublishedBABY-HUGstudy, considerationmust nowbegiventoofferingHUtoall childrenwithSSorSb0. (13)ChronicTransfusionThe suppression of endogenous RBC production by reg-ular transfusionof donor RBCs is another means bywhichcomplicationsof SCDmaybeameliorated. Theclearest indications for chronic transfusions are for bothprimary andsecondary stroke prevention. Short- andlong-termchronictransfusionsalsohavebeenusedtotreat complications such as frequent pain, severe or fre-quentACS, andgrowthfailure, amongothers. Simpletransfusion is the most commonly used method forRBC delivery in chronic transfusions. This method car-ries with it the ubiquitous problem of iron overload, be-cause each milliliter of transfused blood contains between0.5and1mgof elemental iron, whichapproximatesnormal daily absorption. Iron loading occurs primarilyin the liver, heart, and endocrine glands in patients withblooddisorders sicklecelldisease202PediatricsinReviewVol.33No.5May2012SCD, and severe overload can result in morbidity andmortality.The treatment of iron overload requires an exogenousironchelatorbecausehumanslackamechanismtoin-crease excretion of the excess iron. Before 2007, the onlyavailable ironchelator (deferroxamine) inthe UnitedStates requiredsubcutaneous administrationfor 10to12 hours per day, 5 to 7 days per week. Adherence tosucha medicationregimenwas understandably low,so severe iron overload developed in many chronicallytransfused patients with SCD. In 2007, an oral iron che-lator (deferasirox) was licensed. Deferasirox appears tobe as efcacious as deferroxamine in reducing ironburden.In addition to iron overload, transfusion-related in-fection and alloantibody formation are other potentialcomplications of chronic transfusions. Improved donorselection policies and careful nucleic acid based-testinghave greatly reduced, but not eliminated, the likelihoodof transfusion-relatedinfection. The riskof alloanti-bodyformationmaybemitigatedbyextendedRBCcross-matching and programs to match donors and re-cipients byraceandethnicity. Exchangetransfusion,either bymanual exchangeor erythrocytopheresis, isan alternative to simple transfusion and appears togreatly decrease ironloadinginpatients onchronictransfusions.HematopoieticBoneMarrowTransplantationHSCT remains the only curative option for children withSCD. Transplantation works by replacing sickle erythro-cyte progenitors with normal erythrocyte progenitors inthe bone marrow. HSCT typically is reserved for patientsaffectedbysevereor life-threateningcomplications ofSCD, including stroke and ACS.The most important risks of HSCTinclude peri-transplantmortality (frequently from infection), graft-versus-hostdisease, graft failure, and conditioning-induced infertility.Limitations to the use of HSCT include a paucity ofmatched siblings and poor representation of minorities inthebonemarrowdonorpool. UnrelatedHSCTandreduced intensity conditioning regimens have been pub-lished recently but require further exploration in the clin-ical trial setting.EmergingTherapeuticsRecently, a variety of new therapies have been suggestedfor SCD. Most tantalizing is the potential of gene therapyvia the insertion of a normalb globin org globin geneintoa patients ownhematopoietic precursors. Bonemarrowhas been the traditional source of hematopoieticstem cells, although the recent recognition that plurip-otent stemcells maybeinducedfromskincells maymaketheproductionof correctedhematopoieticpre-cursors less invasive and painful. Other emerging thera-peuticscurrentlyunderdevelopmentforpatientswithSCDincludenovelagentsaimedatinducingHgFex-pression, novel anti-inammatory or antithromboticagents to treat or prevent sickle cell complications,in-halednitricoxide, HSCTfromunrelateddonors, andreduced intensity conditioning for HSCT, amongothers.QualityofCareThe provision of care to patients with SCD in the UnitedStatesoccurswithinacomplextapestryofsocietal andpersonal interactions. Theacutecomplicationsof SCDlead to frequent emergency department visits and hospi-talizationsforsomepatients. Unfortunately, studiesofpatient experiences andclinicianattitudes inboththeemergency department and inpatient settings have dem-onstrated frequent distrust between patients and providers.Patients describe both over- and undertreatment and lackof involvement in decision-making.Thequality-of-careprovidedvariesdependingontherarity and severity of a given complication and the experi-ence of the hospital and its personnel with SCD patients.Recently,therstsetofrigorouslydevelopedquality-of-care indicators for childrenwithSCDwere published.(14) These indicators establish a benchmark that will allowprovidersandhealth-careorganizationstomeasuretheirperformance in SCD care, and as changes are made to im-prove performance, the SCD patients experience of carealso may begin to improve.PrognosisandSurvivalIn spite of the many complications that may afict chil-dren who have SCD, their prognosis has improved in pastdecades. Before routine newborn screening and pneumo-coccal prophylaxis, deathfromIPD, splenicsequestra-tion, ACSor other severecomplications of SCDwasa common occurrence in childhood. Recent studies fromcohortsintheUnitedStatesandtheUnitedKingdomsuggest that deathinchildhoodisbecominganinfre-quent event, with w95% of children with SCD survivingtoage18years. (15)Unfortunately, theyoungadultyears, followingtransitiontoadult care, appeartobea high-risk period for individuals with SCD, which hasledtoarecent emphasis onimprovingthetransitionprocess, with the long-term goals of improving qualityof life, quality of medical care, and survival for patientswith SCD.blooddisorders sicklecelldiseasePediatricsinReviewVol.33No.5May2012 203References1. Hassell KL. Population estimates of sickle cell disease in the U.S.Am J Prev Med. 2010;38(suppl 4):S512S5212. Bunn HF, Nathan DG, Dover GJ, et al. Pulmonary hypertensionand nitric oxide depletion in sickle cell disease. Blood. 2010;116(5):6876923. Gladwin MT, Barst RJ, Castro OL, et al. Pulmonary hyperten-sion and NO in sickle cell. Blood. 2010;116(5):8528544. SerjeantGR, SerjeantBE. SickleCell Disease. 3rded. Oxford,United Kindgom: Oxford University Press; 20015. GastonMH, VerterJI, WoodsG, etal. Prophylaxiswithoralpenicillininchildrenwithsicklecell anemia. Arandomizedtrial.N Engl J Med. 1986;314(25):159315996. Falletta JM, Woods GM, Verter JI, et al. Discontinuing penicillinprophylaxis in children with sickle cell anemia. ProphylacticPenicillin Study II. J Pediatr. 1995;127(5):6856907. Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasivepneumococcal diseaseamongindividuals withsicklecell diseasebeforeandaftertheintroductionofthepneumococcal conjugatevaccine. Clin Infect Dis. 2007;44(11):142814338. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovas-cularaccidentsinsicklecell disease: ratesandriskfactors. Blood.1998;91(1):2882949. Adams RJ, McKie VC, Hsu L, et al. Prevention of arst strokebytransfusions inchildrenwithsicklecell anemiaandabnormalresults ontranscranial Doppler ultrasonography. NEngl J Med.1998;339(1):51110. Kwiatkowski JL, ZimmermanRA, PollockAN, et al. Silentinfarctsinyoungchildrenwithsicklecelldisease.BrJHaematol.2009;146(3):30030511. Rogers ZR. Priapism in sickle cell disease. Hematol Oncol ClinNorth Am. 2005;19(5):917928, viii12. StrouseJJ, LanzkronS, BeachMC, et al. Hydroxyureaforsicklecell disease: asystematicreviewforefcacyandtoxicityinchildren. Pediatrics. 2008;122(6):1332134213. WangWC, WareRE, Miller ST, et al; BABYHUGinves-tigators. Hydroxycarbamide in very young children with sickle-cellanaemia: a multicentre, randomised, controlled trial (BABY HUG).Lancet. 2011;377(9778):1663167214. Wang CJ, Kavanagh PL, Little AA, et al. Quality-of-careindicators for childrenwithsicklecell disease. Pediatrics. 2011;128(3):48449315. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improvedsurvival ofchildren and adolescents with sickle celldisease. Blood.2010;115(17):34473452SummarySicklecelldisease(SCD)isaheterogeneousgroupofprevalent, potentiallylife-threatening, chronicdisordersofhemoglobin(Hgb).HgbpolymerizationunderliesthepathophysiologyofSCD.ChildrenwhohaveSCDbenetfromregularhealthmaintenancevisitswithapediatrichematologistandaprimarycarepediatrician.The high incidence of invasive pneumococcal disease(IPD)inSCDjustiesnewbornscreening, dailyprophylacticpenicillin, andimmunizationwiththepneumococcal conjugateandpolysaccharidevaccines.Vaso-occlusivepaincrisesaretheclinical hallmarkofSCDandoccurwithincreasingfrequencythroughchildhood. Theseepisodeswarrantaggressivetreatmentwith analgesics andhydrationandmaybepreventedwithhydroxyurea(HU)therapy.AnnualtranscranialDoppler(TCD)screeningforpatients ages 2 to 16 years identies those at high riskforacutestroke, andregularbloodtransfusionscanreducethisriskgreatly.CommonindicationsforinitiatingHUtherapyhavebeensevereorfrequentvaso-occlusivecrisesoracutechestsyndrome, butthistherapymaybeconsideredinyoungerandlesssymptomaticpatients.TheprognosisforchildrenwithSCDhasimproved,withthevastmajoritysurvivingintoadulthood,promptingafocusonimprovingtheprocessoftransitiontoadultcare.blooddisorders sicklecelldisease204PediatricsinReviewVol.33No.5May2012PIRQuizThis quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Since January 2012, learners cantakePediatricsinReviewquizzesandclaimcreditonlineonly.Nopaperanswerformwillbeprintedinthejournal.NewMinimumPerformanceLevelRequirementsPerthe2010revisionoftheAmericanMedicalAssociation(AMA)PhysiciansRecognitionAward(PRA)andcreditsystem,a minimum performance level must be established on enduring material and journal-based CME activities that are certied for AMAPRACategory1CreditTM.Inordertosuccessfullycomplete2012PediatricsinReviewarticlesforAMAPRACategory1CreditTM,learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of theeducationalpurposeand/orobjectivesofthisactivity.Starting with2012 Pediatrics in Review, AMAPRA Category 1 CreditTMcan be claimed only if 60% or more of thequestions areanswered correctly.If youscore less than 60% on theassessment,you willbe given additionalopportunities toanswer questionsuntilanoverall60%orgreaterscoreisachieved.1. Neonatal screeninghas identiedaninfant withsicklecell anemia. Whichof thefollowingis themostappropriatemethodofprotectionagainstinvasivepneumococcaldisease?A. Begindailyprophylacticpenicillinat2yearsofage;administerpneumococcalpolysaccharidevaccineinsteadofpneumococcalconjugatevaccineatrecommendedintervalsforallchildren.B. Begin daily prophylactic penicillin at 2 years of age; pneumococcal conjugate vaccine as recommended forallchildren, andatleasttwodosesofpneumococcalpolysaccharidevaccineat2and5years.C. Begin daily prophylactic penicillin before 2 months of age; administer pneumococcal conjugate vaccine asrecommended for all children and at least two doses of pneumococcal polysaccharide vaccine at 2 and 5years.D. Begindailyprophylacticpenicillinbefore2monthsofage;administerpneumococcalconjugatevaccineinsteadofpneumococcalpolysaccharidevaccineatrecommendedintervalsforallchildren.E. Begindailyprophylacticpenicillinbefore2monthsofage;administerpneumococcalpolysaccharidevaccine at 2, 4, and 6 months of age and at least two doses of pneumococcal conjugate vaccine at 2 and 5years.2. A 3-year-old girl with sickle cell anemia presents with fatigue and malaise for the last 3 days. Her mother feelsthat the girl appears much paler than usual. Examination reveals a pale child with temperature 37.4C, heartrate125beatsperminute, respirations28perminute, andbloodpressure90/50mmHg.Therestofthephysical examination is unremarkable. Complete blood count reveals a hemoglobin level of 4 G/dL, WBC 5,400/mLwith34%neutrophils, 48%lymphocytes, and18%monocytes, andplatelets250,000/mL.Reticulocytecountis0.4%.Whichofthefollowingbestexplainsthischildsanemia?A. Excessivelysisofirreversiblesicklecells.B. Impairedreleaseoferythrocytesfrombonemarrow.C. Maturationarrestoferythrocyteprecursorsinthebonemarrow.D. Replacementofbonemarrowwithmonocytes.E. Sequestrationoferythrocytesinspleen.3. A4-year-oldgirl withsicklecell disease(genotypeSb0) presents withexcruciatingpaininbothlowerextremitiesforthelast12hours. Shedescribesherpainas9/10belowtherightkneeand6/10belowtheleftknee.Shehasapetturtle, andherimmunizationrecordisunavailable.Physicalexaminationrevealstemperature 38.6C, respirations 26 per minute, heart rate 110 beats per minute, and blood pressure 110/78mmHg. There is mild erythema and moderate swelling over the upper medial surface over right tibia with pointtenderness.Whichofthefollowingisthemostimportantriskfactorforthispresentation?A. Elevatedfetalhemoglobinconcentration.B. GenotypeSb0.C. Havingaturtleasapet.D. Inadequateimmunization.E. Lowbaselinehemoglobin.blooddisorders sicklecelldiseasePediatricsinReviewVol.33No.5May2012 2054. A7-year-oldboywithsicklecell disease(genotypeSS)presentswithdysphasiaandright-sidedweakness.Physicalexaminationrevealsnormalvitalsigns.Thereisdepressionofrightangleofmouthandweaknessofrightupperandlowerextremities.Whichofthefollowingannualscreeningtestswouldhavebeenmosthelpfulinpredictingtheriskofthiscomplication?A. Comprehensiveexaminationbyneurologist.B. Computedtomographyofhead.C. Magneticresonanceimagingofhead.D. MeasurementofhemoglobinSpercentage.E. TranscranialDopplerultrasonography.5. A 15-year-old boy with sickle cell disease (genotype SS) has had several vaso-occlusive crises. Which of thefollowingstatementsaftertreatmentwithhydroxyureaforthispatientismostaccurate?A. Baselinehemoglobinlevelwillbelower.B. CellularDNArepairmechanismsareimpaired.C. Increasedcirculatingneutrophilnumberswillofferprotectionagainstbacterialinfection.D. Increasedexpressionoffetalhemoglobinwilloccur.E. TranscranialDopplervelocitieswillincrease.CondolencesThe staff of Pediatrics in Review has lost another special colleague and friend. Dr. GregoryLiptak, a skilledand compassionate developmental pediatrician and member of our EditorialBoard, diedonMarch3, 2012, andwillbemissedbyallofus.blooddisorders sicklecelldisease206PediatricsinReviewVol.33No.5May2012